We plan to 1) elucidate the complete primary structure of each of the four types of collagens known to exist in various human tissues, including the amino acid sequence and the post-synthetic modifications such as hyrdroxylation of prolyl and lysyl residues, glycosylation of the hydroxy-lysyl residues and the nature and the location of the interchain crosslinks; 2) examine for abnormalities in the above parameters of collagens present in various pathologic tissues of patients with a wide variety of connective tissue disorders; 3) examine for alterations in tissue-specific distributions of the various types of collagens as a function of disease process; and 4) investigate the metabolism of collagen in diseased as compared to normal tissues using in vitro tissue culture to define the various biosynthetic and catabolic steps involved. Specific diseases to be studied include a group of heritable connective tissue disorders, homocystinuria, osteogenesis imperfecta, ochronosis, Marfan syndrome, and pseudoxanthoma elasticum, as well as a group of acquired disorders with a major emphasis on progressive systemic sclerosis (scleroderma). In parallel, a major effort will be devoted to investigate the nature and the mechanisms whereby collagen and collagen-derived peptides exert biologic effects on various inflammatory cells, macrophages and fibroblasts in particular, pinpointing the salient molecular features of the collagen structure involved in the interaction. In addition, we plan to extend our recent observations suggesting possible involvement of cell-mediated immunity against collagen in scleroderma to other inflammatory rheumatic diseases and investigate possible mechanisms of fibroblast activation by the products of the immune reaction.